1. Field of the Invention
The present invention relates to the medical pharmaceutical field and, more specifically, the field of preparations for topical ophthalmic use to be administered by means of iontophoresis to perform the cross-linking (CXL) of corneal collagen useful in the treatment of keratoconus, in particular an improved formulation of an ophthalmic composition containing riboflavin.
2. Description of the Related Art
The collagen cross-linking induced by riboflavin and UV-A, is a practice widely used in ophthalmology, it consists in the photopolymerization of stromal collagen fibrils with the purpose of increasing its rigidity and resistance to progressive keratoectasia of keratoconus through the combined action of a photosensitizer and light-absorbing substance, the riboflavin precisely, by irradiation with ultraviolet light from UV-A type illuminator.
The purpose of the present invention is to provide an ophthalmic solution of riboflavin, as improved cross-linking agent, to be administered by means of iontophoresis in the practice of the treatment of keratoconus, or of other ectatic corneal diseases, having improved permeation and penetration characteristics in the corneal stroma, considerably reducing the time required for the treatment and improving performance and therapeutic outcomes.
Similarly to the brain, eye is protected by biological barriers (the blood-eye barrier, the blood-vitreous barrier) that make difficult the administration of medicaments at sufficient concentration, especially in the posterior segments of the eye. Through the systemic via (by oral or intravenous administration) only a small fraction of the initial amount of drug may be delivered to interior eye tissues, so it is insufficient.
As topical application of eye drops fails to treat the posterior segment of the eye, the penetration is very limited (normally less than 5%), techniques for local administration of medicaments to the eye have been developed and are subjected to continuous and intense study to improve its efficiency. The direct injection around the eyeball (peribulbar, retrobulbar), or within the eyeball (intraocular), is very traumatic. The photodynamic therapy, consisting in the injection of the medicament and in its systemic activation in situ using a laser at specific wavelengths, takes advantage of the transparency of the cornea but it has the disadvantage that the patient must remain in the dark, the medicament must be modified by the addition of a photosensitizing agent preventing the active principle from acting before it is activated by light, also requires the use of special and expensive instrumentation in order to be carried out. Numerous devices designed to convey medicaments in a continuous or programmed manner by the use of medicament tanks placed on the surface of the eye have been also developed, said devices are therefore non-invasive, or in the form of lenses or rings in the conjunctival sac. However, the passage of substance to the posterior segment of the eye is limited, therefore the use of these devices is limited to the treatment of pathologies of the anterior ocular segment, for example, for the treatment of conjunctivitis. Intraocular implants for the programmed release of medicaments surgically positioned in the vitreous humor have the serious risk to damage the retina by contact, since incisions of relatively large size (5 mm) are required to place the implant. Another significant drawback concerns the possible need to replace the implant, or to intervene to interrupt or modify the treatment as a function of how the disease responds to treatment.
In order to improve the corneal absorption of the riboflavin, commonly used as a photosensitizing and curing agent in the process of corneal cross-linking, without having to resort to removal of corneal epithelium, and to obtain in such a way a non-invasive corneal cross-linking, eliminating or reducing anesthesia and resulting in a more rapid healing, patent application WO 2010/023705 has suggested the use of absorption enhancers, including EDTA associated with tromethamine and/or salts of EDTA associated with tromethamine, to form an ophthalmic composition administered in the form of eye drops to be instilled on the corneal surface.
Another possible solution is to use ocular iontophoresis.
This is another technique for administrating active ingredients with therapeutic action which allows to reduce most of the disadvantages of other techniques for ocular administration. In fact it makes possible, in a non-invasive manner, to reach concentrations and residence times in the eye, and hence transfer efficiencies, equal to or greater than those obtained with other techniques of the state of the art.
The principle underlying the iontophoresis involves the application of an electric field to an electrolyte composition containing at least one medicament in order to transport the medicament or medicaments in the body through biological membranes. The technique has long been clinically used in dermatology, in the treatment of osteoarticular disorders, but more recently has proved being particularly suitable for transferring active ingredients and drugs into the eye.
However, because the eye is extremely different from most of the organs of the other body districts, ocular iontophoresis must submit technical specificities different from those of other types of iontophoresis (intensity and current density, duration and control of the applied electric field, physical aspects of the chemical substances to be administered, electrochemical phenomena that occur in the solution during administration).
In particular, international patent application WO 2011/130356 claims a method to activate the cross-linking in at least one component of the eye comprising the transport of the electrically charged cross-linking agent to the ocular component pushing it in depth using the iontophoretic process and the activation of the cross-linking agent conveying an initiation element to the eyepiece element, wherein the eyepiece element is the cornea, the limbus, the sclera and the retina. According to the teachings of said patent application the cross-linking agent, such as riboflavin, can be combined in various concentrations with other agents such as EDTA, benzalkonium chloride, or an alcohol to promote the further transfer across the corneal surface. However, the description does not define amounts or concentrations of the various components of the cross-linking agent.
There is an ongoing debate in the ophthalmic field about the best way to transfer to the cornea riboflavin to perform cross-linking of corneal collagen, the results of clinical studies indicate that the iontophoretic application of riboflavin should decrease processing time and eliminate the recourse to corneal epithelium removal before treatment. The internet publication of the document of George Waring: “Old technique, new delivery”, Ophthalmology Times Conference Brief, Oct. 22, 2011, URL: http://ophthalmologytimes.modernmedicine.com/ophthalmologytimes/ModernMedicine+Now/Old-technique-new-delivery/ArticleStandard/Article/detail/745363, discloses that the iontophoretic treatment accelerating the riboflavin transfer eliminates the need of corneal epithelium removal.
The applicants of the present patent application have already described in patent application WO 2012/095877, filed on 12 Jan. 2011, the use of iontophoresis to deliver ophthalmic compositions, preferably containing riboflavin or other agents promoting cross-linking, designed to permeate the corneal stroma in the practice of corneal cross-linking of collagen in the treatment of keratoconus and other ectatic conditions of the eye. Due to the increased transfer efficiency promoted by the electric current, the administration time is significantly reduced, and the procedure is much more comfortable for the patient.
The ophthalmic compositions described in the aforementioned patent application are specifically designed to increase their transfer ability within and through the eye, by means of iontophoresis. In particular, the compositions described are based on riboflavin, between 0.1 and 1%, or other cross-linking agents that at the same time are also characterized by buffering properties, such as sodium phosphate. In such a way the described compositions improve permeation and penetration in the corneal stroma without having to proceed to the removal of the corneal epithelium in the treatment of keratoconus, or of other corneal ectatic diseases, by means of cross-linking corneal. According to said patent application, the ophthalmic solutions to be transferred by means of iontophoresis must have a initial value of pH in the range between 5 and 8 in order to act as a buffering agent and reach a final value not greater than 9. Furthermore, the presence of dextran guarantees a good adhesiveness to the ocular surface, ensures a better contact and thus a better permeation of the corneal stroma by the riboflavin solution.
However, despite the considerable improvement provided by the ocular iontophoretic administration, always remains particularly felt the need to improve the effectiveness of the ocular transfer by means of iontophoresis in order to further reduce the risks of causing burns, irritations and general toxicity phenomena in the tissues that in the long may limit the application of ocular iontophoresis. It would be desirable to further reduce the time to achieve iontophoresis to reduce the potential risks during the execution of the process and improve the comfort of the patient.
The parameters on which the expert is able to intervene in order to improve the effectiveness and the success of the ocular iontophoretic procedure are many and of different nature, in fact, they relate to: the area of application of the electric field, sclera rather than cornea, this latter particularly delicate; minimizing the density of the electric field, the application area and the electrode area; controlling the intensity of the electric field applied so as to achieve a good reproducibility; limiting the application; and finally, the characteristics of the solution to be transferred.